X-154031360-G-C

Position:

• chrX-154031360-G-C

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000453960.7(MECP2):​c.504C>G​(p.Asp168Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D168G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 ENST00000453960.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.08

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PS1: Transcript ENST00000453960.7 (MECP2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 393489
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in ENST00000453960.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154031361-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 143583.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant X-154031360-G-C is Pathogenic according to our data. Variant chrX-154031360-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 95196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031360-G-C is described in Lovd as [Likely_pathogenic]. Variant chrX-154031360-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.504C>G	p.Asp168Glu	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.468C>G	p.Asp156Glu	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.504C>G	p.Asp168Glu	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.468C>G	p.Asp156Glu	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:7

Pathogenic, no assertion criteria provided	research	RettBASE	Apr 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Nov 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 01, 2022	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS4, PS2_MOD, PS1_MOD, PM1, PM5, PM2_SUP, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 08, 2024	This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 15737703, 16473305, 12075485, 27354166, 20728410, 19722030, 23103540, 30781346, 26984561, 31645865, 19652677, 11524741, 21982064, 16672765,ClinVar Variation ID: 95196). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). (PMID: 15737703) Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2022	Published functional studies demonstrate that the D156E variant results in impaired heterochromatin binding, reduced transcriptional repression, and destabilization of the MeCP2 protein (Kudo et al., 2003; Kucukkal et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19722030, 26418480, 29655203, 32472557, 10805343, 21831886, 12843318, 26984561, 12075485, 11524741) -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 156 of the MECP2 protein (p.Asp156Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 11524741, 12075485, 15737703, 16473305, 16672765, 19722030, 22182064, 26984561, 27354166). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 95196). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function. Experimental studies have shown that this missense change affects MECP2 function (PMID: 12843318, 26418480). This variant disrupts the p.Asp156 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been observed in individuals with MECP2-related conditions (PMID: 11309679, 15737703, 18021529, 22182064), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.86	D;D;T;T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.7	D;D;.;.;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;.;.;.
Sift4G	Benign	0.16	T;D;.;T;D
Polyphen		0.99	D;D;.;.;.
Vest4		0.74
MutPred		0.93		Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);.;.;
MVP		1.0
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61748408; hg19: chrX-153296811;